Preparation of 4-aminodibenzo(a,d) cycloalken-5-ones



United States Patent 3,424,796 PREPARATION OF 4-AMINODIBENZO[a,d] CYCLOALKEN-S-ONES Eugene E. Galantay, Morristown, and Hans Ott, Convent Station, N.J., assignors to Sandoz Inc., Hanover, N]. No Drawing. Filed Mar. 30, 1965, Ser. No. 444,023 US. Cl. 260576 3 Claims Int. Cl. C07c 87/64 ABSTRACT OF THE DISCLOSURE Pharmaceutically useful 4-amino-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-ones and 4-amino-5,10,l1,12- tetrahydrodibenzo[a,d]cycloocten S-ones are obtainable by cyclization of the appropriate 6-w-phenyl(lower)alkylanthranilic acid.

The present invention is directed to the preparation of 4-amino-dibenzocycloalkenones, particularly pharmaceutically acceptable 4-amino-10,1l-dihydro-SH-dibenzo[a,d] cyclohepten-S-ones and 4-amino-5,l0,l1,12-tetrahydrodibenzo[a,d]cycloocten-5-ones. The ring structure of these compounds is depicted by the formula O R I I R2 I wherein X is either dimethylene (CH CH or trimethylene (CH CH -CH and N(R )R is an amino moiety.

More specifically:

Compounds I wherein R and/ or R is a hydrogen atom are intermediates for the preparation of compounds I wherein at least one of said hydrogens is replaced. Compounds I are useful as hypotensive-antihypertensives. They are administered either orally or parenterally in daily doses of from 25 to 75 milligrams.

Each of the pharmaceutically active compounds I may be, e.g., incorporated for oral administration in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to 10 percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. An exemplary tabletting formation with compound I as active ingredient is Parts Title compound of Example 16 15 Tragacanth 2 Lactose 74.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5 Alcohol SD30 Purified water The process for the preparation of those compounds wherein X is trimethylene employs the same starting material, but requires several additional steps to introduce the third CH group. The parallel processes are represented graphically:

on2)..-c112cHr- H RINR In the graphic representation n is in the intermediates (a) for compounds I wherein X is dimethylene, and n is 1 in the intermediates (b) for compounds I wherein X is trimethylene.

A is the reaction of 3,6-dichlorophthalic anhydride with malonic acid in pyridine.

B is the reaction of VII with benzaldehyde in a basic medium, e.g. aqueous ethanol containing sodium hydroxide.

C is the hydrogenation of VIII, followed by dehydration.

D is the condensation of 3,6-dichlorophthalic anhydride with phenylacetic acid to phthalide lIIa. {See Ukrainskii Khimicheskii Zhurnal, 19, 421 to 428 (1953).]

E is the reduction of III with hydriodic acid and red phosphorus. This reduction affects only the double bond of III and leaves the lactone ring unchanged. [The unchlorinated analogue of compound IIIa is reduced under these conditions to Z-B-phenethylbenzoic acid.]

F is the aminolysis (or ammonolysis) of IV (effected quantitatively without reaction with the lactone ring).

G is a saponification of the lactone group of V, followed by catalytic reduction (hydrogenation).

H is the ring closure (cyclization) with polyphosphoric acid.

The process is based upon the polyphosphoric acid cyclization of 6-B-phenethyland 6 'y phenylpropyl-anthranilic acids VI to compounds I, wherein each of R and R is, independently, either a hydrogen atom (--H) or lower alkyl. If the amino group in the anthranilic acid V1 is primary or secondary, i.e. if either R and/or R is a hydrogen atom, it must be protected prior to cyclization. This protection is best achieved by para-toluenesulfonation or methanesulfonation. After the cyclization is effected, either of these groups is readily hydrolyzed. They are thus removed when the polyphosphoric acid cyclization mixture is worked up in the usual way by pouring same onto ice.

The examples directed to steps E, F, G and H apply to both the preparation of the cycloheptenones and the preparation of the cyclooctenones. In the examples the parts and the percentages are by weight unless otherwise specified, and the temperatures are in degrees centigrade. The relationship between parts by weight and parts by volume is the same as that between the kilogram and the liter.

EXAMPLE 1 3-hydroxy-3-methyl-4,7 -dich1orophthalide OH Cl Heat slowly a mixture of 23.4 parts of 3,6-dichlorophthalic anhydride, 13.2 parts of malonic acid and 106 parts by volume of dry pyridine to 90 to 100, and maintain same at said temperature until (3 to 4 hours) carbon dioxide evolution ceases. Thereafter, add to the resultant 100 parts by volume of water, and acidify the product to 4 pH 2 with 5 N hydrochloric acid. There are thus obtained 23.2 parts of title compound, melting point (M.-P.) to 146. After recrystallization from benzene, the pure title compound melts at 149.

EXAMPLE 2 3-hydroxy-3-B-styryl-4,7-dichlorophthalide To a solution of 19.6 parts of the title compound of Example 1 and 9.78 parts of benzaldehyde in 150 parts by volume of ethanol add 18.36 parts by volume of 5.5 N (aq.) sodium hydroxide. Maintain the resulting mixture at room temperature (20) for 90 minutes, and then add thereto 900 parts by volume of water. Concentrate the resultant in vacuo to 190 parts by volume to remove most of the ethanol. Extract the concentrate with diethylether, and discard the ether extracts. The aqueous phase is essentially a solution of the sodium salt of the title compound, which need not be isolated for step C. The free title compound is obtained, however, by acidification of the above solution, M.P. 153 to 156.

EXAMPLE 3 3-fl-phenethylidene-4,7-dichlorophthalide Add to said aqueous solution of Example 2 Raney nickel catalyst, and hydrogenate the obtained mixture at 50 p.s.i.g. and room temperature until no more hydrogen is taken up. Filter off the catalyst, acidify the filtrate with 5 N hydrochloric acid to pH 2, and extract with ethyl acetate to obtain 22.2 parts of a yellow gum. Heat the extracted gum to 200 under 90 millimeters (mm.) pressure for 180 minutes. Cool and stir the product with 30 parts by volume of methanol to obtain 8.35 parts of title compound, M.P. 140 to 142.

EXAMPLE 4 3-benzyl-4,7-dichlorophthalide residue from diethylether/petroleum ether to obtain 19.5 parts of title compound, Ml. 94 to 96.

EXAMPLE 3-fl-phenethyl-4,7-dichlorophthalide II 01 O Reflux for 2 hours a mixture of 7.4 parts of B-B-phenethylidene-4,7-dichlorophthalide, 1.63 parts of red phosphorus and 34 parts by volume of 58% (aq.) hydriodic acid. After adding 1.6 parts of red phosphorus, continue refluxing for another 16 hours. On cooling the thusrefluxed mixture, an upper layer is formed; this layer solidifies. Filter, Wash the solids With water and with hot ammonium hydroxide. Then crystallize the washed solids from diethylether to obtain 5.85 parts of title compound,

M.P. 124 to 126.

. EXAMPLE 6 3-benzyl-4-chloro-7-rnethylaminophthalide o1 CHz-CH I (l CH (l IIH2 Heat overnight at 160 in a closed system a mixture of 8.33 parts of 3-benZyl-4,7-dichlorophthalide and 100 parts by volume of 20% ethanolic ammonia. Evaporate the product to dryness. Dissolve the residue in methylene chloride, and Wash the obtained methylene chloride solution with water. Dry and evaporate the thus-washed solution to obtain the title compound.

EXAMPLE 8 3-benzyl-4-chloro-7-dimethylaminophthalide o1 CHr-CH I NCH3 Heat overnight at 160 in a closed system a mixture of 8.33 parts of 3-benzyl-4,7-dichlorophtl1alide and 100 parts by volume of 20% ethanolic dimethylamine. Evaporate the product to dryness. Dissolve the residue in methylene chloride, and Wash the obtained methylene chloride solu- 6 tion with Water. Dry and evaporate the thus-Washed solution to obtain the title compound.

EXAMPLE 9 3-benzyl-4-chloro-7-piperidylphthalide CH2CH 0 Heat overnight at 160 in a pressure apparatus a mixture of 8.33 parts of 3-benzyl-4,7-dichlorophthalide and parts by volume of 20% ethanolic piperidine. Evaporate the product to dryness. Dissolve the residue in methylene chloride, and wash the obtained methylene chloride solution with water. Dry and evaporate the thus-washed solution to obtain the title compound.

EXAMPLE 1O 3-,8-phenethyl-4-chloro-7-piperidylphthalide Heat at in a closed apparatus for 24 hours a mixture of 2.5 parts of 3-,B-phenethyl-4,7-dichlorophthalide with 40 parts by volume of 50% ethanolic piperidine. Cool the obtained mixture to room temperature and evaporate same to dryness to obtain the title compound.

EXAMPLE 11 3 -B-phenethyl-4-chloro-7-dimethylaminophthalide gong-onion ll Heat at 150 in a pressure apparatus for 24 hours a mixture of 2.5 parts of 3-,8-phenethyl-4,7-dichlorophthalide with 40 parts by volume of 50% ethanolic dimethylamine. Cool the obtained mixture to room temperature and evaporate same to dryness to obtain the title compound.

EXAMPLE 12 3-fl-phenethyl-4-chloro-7-aminophthalide o1 CHzOH2CH Heat for 24 hours in a closed system at 150 a mixture of 2.5 parts of 3-,8-phenethyl-4,7-dichlorophthalide with 40 parts by volume of 50% ethanolic ammonia. Cool the obtained mixture to room temperature and evaporate same to dryness to obtain the title compound.

EXAMPLE 13 3-f3phenethyl-4-chloro-7-methylaminophthalide o1 carom-on Heat in a closed system for 24 hours at 150 a mixture of 2.5 parts of 3-fl-phenethyl-4,7-dichlorophtha1ide with 40 parts by volume of a 50% ethanolic methylamine solution. Cool the obtained mixture to room temperature, evaporate same to dryness, and recrystallize the solid residue from methanol to obtain the title compound, M.P. 70 to 71.

EXAMPLE 14 6-18-phenethyl-N-methylanthranilic acid CHz-CH HOOG Reflux for 15 minutes a mixture of 7.33 parts of 3- benzyl-4-chloro-7-methylaminophthalide (title compound of Example 6), 385 parts of potassium hydroxide and 12 parts by volume of water. Evaporate the refluxed material to dryness, and maintain the residue at 170 to 180 for 3 hours.

Add to the thus-treated residue 150 parts by volume of water and 3.8 parts of palladium/carbon catalyst prior to hydrogenating at 80 under 40 p.s.i.g. hydrogen pressure. Cool the hydrogenated product to room temperature, and filter the cooled product from the catalyst. Neutralize the filtrate with hydrochloric acid to precipitate 4.45 parts of title compound, M.P. 123 to 125. Replacing the title compound of Example 6 with an equivalent of that of Example 7, that of Example 8 or that of Example 9 results in the preparation, in the same manner, of the corresponding compound VI.

EXAMPLE N-methyI-G-y-phenylpropylanthranilic acid CHr-CHr-CHz- HOOC Stir a mixture of 30 parts or 3-fl-phenethyl-4-chloro- 7-methylaminophthalide (title compound of Example 13), 15 parts of potassium hydroxide and 50 parts by volume of water at 100 until solution occurs. Dilute the obtained solution With an additional parts by volume of water. Adjust the pH of the thus-diluted product to 8.5 with acetic acid. Add 8 parts of palladium/carbon (10%) catalyst to the resultant, and hydrogenate at 80 under 50 p.s.i.g. of hydrogen. Filter the catalyst from the hydrogenated product, and adjust the pH of the filtrate to about 6 with hydrochloric acid to precipitate the title compound.

Replacing the title compound of Example 13 with an equivalent of that of Example 10, that of Example 11 or that of Example 12 results in the preparation, in the same manner, of the corresponding compound VI.

EXAMPLE 16 4-methylamino-10,1l-dihydro-5H-dibenzo[a,d] cyclohepten-S-one g NH Add 4.4 parts of para-toluenesulfonic acid chloride to a solution (under stirring) of 5 parts of 6-13-phenethyl-N- methylanthranilic acid (title compound of Example 14) in 41 parts by volume of 1 N (aq.) sodium hydroxide and 50 parts by volume of dioxane. After 15 minutes add 20 more parts by volume of 1 N (aq.) sodium hydroxide, and continue stirring for 2 hours (total).

Acidity the product to pH 1 with hydrochloric acid, and extract therefrom with diethylether 7 parts of oil. Heat the oil in admixture with parts of poly phosphoric acid to to for 50 minutes, and pour the obtained product onto ice, Extract material with methylene chloride, and pass the produced methylene chloride solution (after drying same) through 20 parts of alumina. Evaporate the methylene chloride fractions and recrystallize the residue from diethylether to obtain 2.29 parts of title compounds, M.P. 122 to 123.

Replacing the title compound of Example 14 with an equivalent of any of the compounds contemplated in Examples 14 and 15 results in the preparation, in the same manner, of the corresponding Compound I.

Various changes may be made in the intermediates and in the process details without departing from the spirit and scope of the invention or sacrificing its material advantages. The disclosed compounds and the working examples merely provide illustrative embodiments. Reactions A to H are independent of inert substituents on the several aromatic rings.

What is claimed is:

1. A process which comprises:

(a) heating a mixture of 3,6-dichlorophthalic anhydride, malonic acid and dry pyridine at a temperature of from 90 to 100 C. until carbon dioxide evolution ceases, whereby there is obtained 3-hydroxy-3- methyl-4,7-dichlorophthalide;

( b) admixing aqueous sodium hydroxide with a solution of 3-hydroxy-3-methyl-4,idichlorophthalide and benzaldehyde in ethanol to obtain 3-hydroxy-3- styryl-4,7dichlorophthalide;

(c) catalytically hydrogenating 3-hydroxy-3-styryl-4,7-

dichlorophthalide and dehydrating the product to obtain 3-fl-phenethylidine-4,7-dich1orophthalide;

(d) refluxing 3-/3-phenethylidene-4,7-dichlorophthalide in admixture with red phosphorus and hydriodic acid to obtain 3-/8-phenethyl-4,7-dichlorophthalide;

(e) heating at a temperature from 100 C. to reflux a mixture of 3-B-phenethyl-4,7-dichlorophthalide with a solution of methylamine in an inert solvent to obtain 3-p-phenethyl-4chloro-7-methylaminophthalide;

(f) saponifying the lactone moiety of 3-,8-phenethyl-4- chloro-7-rmethylaminophthalide and catalytically hydrogenating the thus-obtained saponification product to obtain N-methyl-6-y-phenylpropylanthranilic acid;

(g) cyclizing the N-p-toluenesulfonyl derivative of the latter with polyphosphoric acid to form 4-methylamino 5,10,11,12 tetrahydrodibenzo[a,d] cycloocten-S-one.

2. A process which comprises cyclizing a 6-substituted (lower) al-kylanthranilic acid, the fi-substituent being fi-phenethyl or vphenylpropyl, with polyphosphoric acid to obtain the corresponding 4-(lower)alkylaminodibenzo [a,d1cycloalken-5-one.

3. A process which comprises cyclizing 6-,B-phenethy1- CHARLES B PARKER Primary Examinen N-(1ower)alky1anthranilic acid with polyphosphoric acid to obtain the corresponding 4-(lower)a1ky1amino-10,11- ES A [E dihydro-SH-dibenzo[a,d]cycIohe tcmS-one. W

References Cited US. Cl. X.R. UNITED STATES PATENTS 260-270, 343.3, 518, 578, 562 3,052,721 9/ 1962 Bernstein et a1. 260-570".5 X-R 

